1. Field of the Invention
This invention relates to a clinically useful medicament having a serotonin antagonism, in particular, that for treating, ameliorating and preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
Myotonia, which seriously restrains daily life, is induced by any of a number of factors or a combination thereof, for example, cervico-omo-brachial syndromes accompanying stiffness or pain in the neck, shoulder, arm, lumbar and dorsal skeletal muscles due to abnormal posture, fatigue, changes in the backbone with ageing etc., shoulder periarthritis accompanying inflammation in the tissues constituting the shoulder joint due to changes in the shoulder joint caused by trauma, etc., and spastic paralysis wherein accelerated limb muscle tonus hinders voluntary movements.
In particular, spastic paralysis is a disease which accompanies limb muscle tonus, stiffening, walking difficulty, etc. and thus seriously restrains daily life.
2. Description of the Prior Art
It has been a practice to treat these diseases mainly with the use of medicaments. At the present stage, central muscle relaxants or peripheral muscle relaxants are administered to patients with these diseases.
Particular examples of used central muscle relaxants include Tolperisone hydrochloride, Baclofen, Tizanidine hydrochloride, Chlorzoxazone and Diazepam.
On the other hand, particular examples of used peripheral muscle relaxants include suxamethonium chloride, Pancuronium bromide and dantrolene sodium.
Central muscle relaxants act selectively on the central nervous system so as to relax muscles. Therefore, it is expected that those action on the upper center would exhibit a more potent muscle relaxant effect. However, there arise at the same time some problems including extrapyramidal symptoms and neurologic manifestations such as sleepiness, sluggishness and atony. Namely, there has been known hitherto no medicament capable of achieving well-balanced principal action and side effects.
Diazepam, which is inherently a minor tranquilizer, is efficacious against diseases accompanying mental symptoms such as anxiety, tension and depression. However, its effect is too potent to merely ameliorate myotonia. With the use of diazepam, therefore, spastic paralysis can be relieved but there arise some problems such as dizziness.
On the other hand, suxamethonium chloride and Pancuronium bromide which are peripheral muscle relaxants are marketed exclusively as injections, which makes the chronic administration thereof difficult.
Dantrolene sodium is processed into injections and preparations for oral use and has a relatively potent muscle relaxant effect. However, it suffers from problems of having only a low margin of safety and frequently inducing muscular atony. Accordingly, it is difficult for those other than medical specialists to administer this medicine.
As discussed above, there has been known hitherto no medicaments for treating and ameliorating myotonia in spastic paralysis etc., which is clinically useful and has a high safety.
Under these circumstances, the present inventors have conducted extensive studies to develop medicaments for treating, ameliorating and preventing spastic paralysis or central muscle relaxants which have a potent effect of ameliorating myotonia while sustaining a high safety and newly paid their attention to compounds having a serotonin antagonism. As a result, they have successfully found that a novel 1,4-substituted cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof has an excellent central muscle relaxant effect and a high safety and thus makes it possible to solve the above problems, thus completing the present invention.
Accordingly, the present invention aims at providing clinically useful novel medicaments which have well-balanced principal action and side effects and make it possible to overcome the problem encountering in the prior art that those acting on the upper center would exhibit a more potent muscle relaxant effect but at the same time suffer from some problems including extrapyramidal symptoms and neurologic manifestations such as sleepiness, sluggishness and weakness.
Because of the anti-serotonin effect, it is expected that the 1,4-substituted cyclic amine derivative (I) of the present invention is moreover usable in preventing, treating and ameliorating depression, emotional disorders, schizophrenia, sleep disturbance, anxiety, spinal cord injury, thrombosis, hypertension, brain circulatory disturbances, peripheral circulatory disturbances, drug addiction, etc.
The 1,4-substituted cyclic amine derivative (I) according to the present invention is represented by the following formula: 
wherein
A, B, C and D are the same or different from one another and each represents methine or nitrogen, provided at least two of them are methine;
the bond represented by the following formula: 
xe2x80x83represents a single or double bond;
T represents methine or nitrogen;
Y and Z are the same or different from each other and each represents methine, nitrogen, a group represented by the following formula: 
xe2x80x83or a group represented by the following formula: 
xe2x80x83provided at least one of them represents nitrogen;
R1 and R2 are the same or different from each other and each represents hydrogen, halogeno, hydroxy, lower alkylsulfonylaminoalkyl, lower halogenated-alkylsulfonylaminoalkyl, 2-pyrrolidinon-1-yl, 1-hydroxy-1-(methoxypyridyl)methyl, methoxypyridylcarbonyl, 1,3-propanesultum-2-yl, lower hydroxypiperidylcarbonylalkyl, lower hydroxyalkylamidoalkyl, lower halogenated-alkylamidoalkyl, lower dihalogenated-alkylamidoalkyl, lower heteroarylamidoalkyl, lower hydroxyalkylamidoalkyl, optionally substituted amino, nitro, lower alkyl, lower alkoxy, lower acyl, lower alkoxyalkoxy, cyano, lower alkylsulfonyl, sulfonylamido, hydroxy-lower alkyl, hydroxy-lower alkoxy, lower alkoxycarbonylamino, lower alkylsulfonylamino, N-lower alkylalkylsulfonylamino, lower acylamino, optionally substituted aminoalkyl, optionally N-substituted lower acylaminoalkyl, optionally substituted aryl, optionally substituted arylsulfonylamino, lower alkylsulfonyloxy, hydroxyiminomethyl, (2-pyrrolidon-1-yl)methyl, (2-piperidon-1-yl)methyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, cycloalkylcarbonylaminoalkyl, optionally substituted ureido, optionally substituted ureido-lower alkyl, succinimido, (succinimido-1-yl)-lower alkyl, amido, optionally substituted carbamoyl, optionally substituted carbamoyl-lower alkyl, optionally substituted thiocarbamoyl-lower alkyl, formyl, aromatic acyl, heteroarylcarbonyl, halogenated lower alkyl, (2-imidazolidinon-1-yl)methyl, (2,4-imidazolidinedion-3-yl)methyl, (2-oxazolidon-3-yl)methyl, (glutarimido-1-yl)methyl, optionally substituted heteroarylhydroxyalkyl, cyano-lower alkyl, 1-hydroxy lower cycloalkyl, (2,4-thiazolidinedion-3-yl)methyl, optionally substituted 4-piperidylmethyl, heteroarylacyl, pyrrolidinylcarbonyl-lower alkyl, optionally substituted aminosulfonylalkyl, carboxy-lower alkyl or lower alkylamidoalkyl; or alternatively R1 and R2 together may form optionally substituted alicycle, optionally substituted heterocycle or alkylenedioxy, provided these rings may be substituted;
R3 represents hydrogen, halogeno, lower alkyl, hydroxy, hydroxy-lower alkyl, lower alkoxy, formyl, optionally substituted aralkyloxy, hydroxy-lower alkoxy, optionally substituted sulfamoyl or optionally N-substituted sulfamoyl-lower alkyl;
R4 represents hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxyalkyl, optionally aryl-substituted aryloxyalkyl or optionally aryl-substituted aralkyloxyalkyl;
R5 represents lower alkyl, lower acyl, lower alkoxycarbonyl, aromatic acyl or a group represented by the following formula:
xe2x80x94Q1xe2x80x94(CH2)sxe2x80x94Q2xe2x80x94R6
xe2x80x83[wherein
Q1 and Q2 are both single bonds, or one of them is a single bond while the other represents oxygen, carbonyl, a group represented by xe2x80x94NHCOxe2x80x94, a group represented by xe2x80x94NHSO2xe2x80x94 or a group represented by  greater than CHxe2x80x94R7 (wherein R7 represents hydroxy, lower alkyl or halogeno):
s represents 0 or an integer of 1 to 6; and
R6 represents optionally substituted aryl, optionally substituted heteroaryl, optionally substituted benzoheteroaryl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzothiazolyl or cyano];
n represents 0 or an integer of 1 to 3;
m represents 0 or an integer of 1 to 6; and
p represents an integer of 1 to 3.
The term xe2x80x9chalogenoxe2x80x9d as used in the above definition particularly means chloro, fluoro, bromo and iodo.
The term xe2x80x9coptionally substituted aminoxe2x80x9d particularly means amino optionally substituted by lower alkyl, optionally substituted aryl, etc.
The term xe2x80x9clower alkylxe2x80x9d particularly means C1-6 alkyl such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl. The term xe2x80x9clower alkoxyxe2x80x9d particularly means those consisting of the above lower alkyl and oxygen bonded thereto such as methoxy, ethoxy and propoxy. The term xe2x80x9clower acylxe2x80x9d particularly means those consisting of lower alkoxy and carbonyl bonded thereto such as acetyl, propionyl and butyryl. The term xe2x80x9clower alkoxyalkoxyxe2x80x9d particularly means the above lower alkoxy further substituted by lower alkoxy such as methoxymethoxy, methoxyethoxy and methoxypropoxy. The term xe2x80x9clower alkylsulfonylxe2x80x9d particularly means the above lower alkyl bonded to sulfonyl (xe2x80x94SO2xe2x80x94) such as methanesulfonyl and ethanesulfonyl. The term xe2x80x9csulfonylamidoxe2x80x9d means those represented by the formula (xe2x80x94SO2NH2). The term xe2x80x9chydroxy-lower alkylxe2x80x9d particularly means the above lower alkyl substituted by one or more hydroxy groups such as hydroxymethyl, hydroxyethyl and hydroxypropyl. The term xe2x80x9clower alkylsulfonylaminoxe2x80x9d particularly means the above lower alkyl bonded to sulfonylamino (xe2x80x94SO2N less than ) such as methanesulfonylamino, ethanesulfonylamino, propanesulfonylamino, butanesulfonylamino and N-methylmethanesulfonylamino. The term xe2x80x9clower acylaminoxe2x80x9d particularly means amino bonded to lower (C2-6) fatty acids such as acetamido, propionamido and butyrylamido.
The term xe2x80x9coptionally N-substituted lower acylaminoalkylxe2x80x9d particularly means the above lower acyl bonded to amino-lower alkyl such as acetamidomethyl, acetamidoethyl, propionamidomethyl and butrylamidomethyl which may be further N-substituted by lower alkyl, etc.
The term xe2x80x9coptionally substituted arylsulfonylaminoxe2x80x9d particularly means aryl bonded to sulfonylamino (xe2x80x94SO2NHxe2x80x94) and optionally further substituted such as benzenesulfonylamino and toluenesulfonylamino. The term xe2x80x9clower alkylsulfonyloxyxe2x80x9d particularly means the above lower alkyl bonded to sulfonyloxy (xe2x80x94SO3xe2x80x94). The term xe2x80x9coptionally substituted aminoalkylxe2x80x9d particularly means amino bonded to the above lower alkyl which may be further N-substituted by lower alkyl, lower alkylsulfonyl, etc.
The term xe2x80x9coptionally substituted arylxe2x80x9d particularly means optionally substituted phenyl, optionally substituted naphthyl, etc. Preferable substituents are ahalogen or a lower alkoxy, and further preferable are fluorine, chlorine and methoxy. And plural substituents may be used, which are the same as or different from one another. The term xe2x80x9coptionally substituted heteroarylxe2x80x9d particularly means optionally substituted pyridyl, pyrazyl, pyrimidyl, pyrrolyl, imidazolyl, pyrazolyl, quinolyl, isoquinolyl, furyl, thienyl, thiazolyl, etc. The term xe2x80x9coptionally substituted aralkylxe2x80x9d particularly means optionally substituted benzyl, phenethyl, phenylpropyl, etc. The term xe2x80x9coptionally substituted heteroarylalkylxe2x80x9d particularly means optionally substituted pyridylmethyl, pyridylethyl, pyrazylethyl, pyridonemethyl, pyrrolidonemethyl, pyrrolylmethyl, imidazolylmethyl, triazolylmethyl, thiazolylmethyl, etc. The term xe2x80x9ccycloalkylcarbonylaminoalkylxe2x80x9d means carbonylaminoalkyl bonded to C3-8 cycloalkyl.
The term xe2x80x9coptionally substituted carbamoyl-lower alkylxe2x80x9d particularly means, for example, carbamoylmethyl (H2NCOCH2xe2x80x94) optionally N-substituted by lower alkyl, cycloalkyl, lower hydorxyalkyl, lower dihydroxyalkyl, lower carbamoylalkylcarbamoylalkyl, lower dialkylaminoalkyl, lower cyanoalkyl, lower alkoxyalkyl, lower halogenated-alkyl, etc. at the 1 or 2 position. The term xe2x80x9coptionally substituted thiocarbamoyl-lower alkylxe2x80x9d particularly means, for example, thiocarbamoylmethyl (H2NCSCH2xe2x80x94) optionally N-substituted by lower alkyl, etc.
The term xe2x80x9cheteroarylcarbonylxe2x80x9d particularly means pyridylcarbonyl, pyrrolylcarbonyl, thaizolylcarbonyl, etc. The term xe2x80x9chalogenated lower alkylxe2x80x9d means lower alkyl substituted with halogeno such as chloromethyl, fluoromethyl, fluoroethyl, etc.
The term xe2x80x9coptionally substituted heteroarylhydroxyalkylxe2x80x9d particularly means pyridylhydroxymethyl, thiazolylhydroxymethyl, pyrimidylhydroxymethyl, pyrrolylhydroxymethyl, etc.
More particularly, the 1,4-substituted cyclic amine derivatives (I) of the present invention are exemplified by the following compounds, though the present invention is not restricted thereto:
(1) 1-[1-(4-fluorophenyl)piperidin-4-yl]indoline,
(2) 1-[1-(4-fluorobenzyl)piperidin-4-yl]indoline,
(3) 1-(1-phenethylpiperidin-4-yl)indoline,
(4) 1-[1-(4-bromophenethyl)piperidin-4-yl]indoline,
(5) 1-[1-(3-chlorophenethyl)piperidin-4-yl]indoline,
(6) 1-[1-(4-chlorophenethyl)piperidin-4-yl]indoline,
(7) 1-[1-(2-fluorophenethyl)piperidin-4-yl]indoline,
(8) 1-[1-(3-fluorophenethyl)piperidin-4-yl]indoline,
(9) 1-[1-(4-fluorophenethyl)piperidin-4-yl]indoline,
(10) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]indoline,
(11) 1-[1-(3,4-difluorophenethyl)piperidin-4-yl]indoline,
(12) 1-[1-(3,5-difluorophenethyl)piperidin-4-yl]indoline,
(13) 1-[1-(4-fluorophenylpropyl)piperidin-4-yl]indoline,
(14) 1-{1-[2-(4-fluorophenyl)propyl]piperidin-4-yl}indoline,
(15) 1-[l-(4-fluorophenylbutyl)piperidin-4-yl]indoline,
(16) 1-[1-(4-fluorophenethyl)piperidin-4-yl]methylindoline,
(17) 1-{2-[1-(4-fluorophenethyl)piperidin-4-yl]ethyl}indoline,
(18) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]indoline,
(19) 1-[1-(3-methoxyphenethyl)piperidin-4-yl]indoline,
(20) 1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline,
(21) 1-[1-(4-cyanophenethyl)piperidin-4-yl]indoline,
(22) 1-[1-(3-hydroxymethylphenethyl)piperidin-4-yl]indoline,
(23) 1-[1-(4-hydroxymethylphenethyl)piperidin-4-yl]indoline,
(24) 1-{1-[4-(2-hydroxyethyl)phenethyl]piperidin-4-yl]indoline,
(25) 1-{4-[(1-hydroxyethyl)phenethyl]piperidin-4-yl}indoline,
(26) 1-{1-[4-(2-hydroxyethoxy)phenethyl]piperidin-4-yl}indoline,
(27) 1-[1-(4-trifluoromethylphenethyl)piperidin-4-yl]indoline,
(28) 1-[1-(4-methanesulfonylphenethyl)piperidin-4-yl]indoline,
(29) 1-[1-(4-nitrophenethyl)piperidin-4-yl]indoline,
(30) 1-[1-(4-aminophenethyl)piperidin-4-yl]indoline,
(31) 1-[1-(4-methylsulfonylaminophenethyl)piperidin-4-yl]indoline and 1-{1-[4-bis(methylsulfonyl)aminophenethyl]piperidin-4-yl}indoline,
(32) 1-[1-(4-acetamidophenethyl)piperidin-4-yl]indoline,
(33) 1-[1-(4-ethylaminophenethyl)piperidin-4-yl]indoline,
(34) 1-[1-(4-hydroxyiminomethylphenethyl)piperidin-4-yl]indoline,
(35) 1-[1-(4-aminomethylphenethyl)piperidin-4-yl]indoline,
(36) 1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indoline,
(37) 1-[1-(4-chloroacetamidomethylphenethyl)piperidin-4-yl]indoline,
(38) 1-[1-(4-methanesulfonylaminomethylphenethyl)-piperidin-4-yl]indoline,
(39) 1-[1-(4-propionylaminomethylphenethyl)piperidin-4-yl]-3-methylindoline,
(40) 1-[1-(4-carbamoylphenethyl)piperidin-4-yl]indoline,
(41) 1-[1-(4-N-isopropylcarbamoylmethylphenethyl)piperidin-4-yl]indoline,
(42) 1-[1-(4-sulfamoylphenethyl)piperidin-4-yl]indoline,
(43) 1-{3-[(2-hydroxyethoxy)phenethyl]piperidin-4-yl}indoline,
(44) 1-{1-[4-(2-dimethylaminoethoxy)phenethyl]piperidin-4-yl}indoline,
(45) 1-{1-[3,4-di (hydroxymethyl)phenethyl]piperidin-4-yl}indoline,
(46) 1-{1-[3,4-(methylenedioxy)phenethyl]piperidin-4-yl}indoline,
(47) 1-{1-[2-(4-chlorophenylsulfonylamino) ethyl]-piperidin-4-yl}indoline,
(48) 1-{1-[2-(4-methoxyphenylsulfonylamino)ethyl]-piperidin-4-yl}indoline,
(49) 1-{1-[2-(4-pyridyl)ethyl]piperidin-4-yl}indoline,
(50) 1-{1-[2-(2-pyridyl)ethyl]piperidin-4-yl}indoline,
(51) 1-{1-[2-(3-pyridyl)ethyl]piperidin-4-yl}indoline,
(52) 1-{1-[2-(2-methoxy-5-pyridyl)ethyl]piperidin-4-yl}indoline,
(53) 1-{1-[2-(3-methoxypyridin-5-yl)ethyl]piperidin-4-yl}indoline,
(54) 1-{1-[2-(2-cyanopyridin-5-yl)ethyl]piperidin-4-yl}indoline,
(55) 1-{1-[2-(2-hydroxymethylpyridin-5-yl)ethyl]-piperidin-4-yl}indoline,
(56) 1-{1-[2-(3-hydroxymethylpyridin-5-yl)ethyl]-piperidin-4-yl}indoline,
(57) 1-[1-(2,6-difluoro-3-pyridylethyl)piperidin-4-yl]indoline,
(58) 1-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}indoline,
(59) 1-{1-[2-(3-thienyl)ethyl]piperidin-4-yl}indoline,
(60) 1-[1-(2-thiazolylethyl)piperidin-4-yl]indoline,
(61) 1-[1-(4-methyl-5-thiazolylethyl)piperidin-4-yl]indoline,
(62) 1-{1-[(indol-3-yl)ethyl]piperidin-4-yl}indoline,
(63) 1-{1-[2-(6-benzothiazolyl)ethyl]piperidin-4-yl}indoline,
(64) 1-[1-(5-methoxy-2-thienyl)ethylpiperidin-4-yl]indoline,
(65) 1-[1-(2-methoxy-5-thiazolyl)ethylpiperidin-4-yl]indoline,
(66) 1-[1-(2-cyano-5-thiazolyl)ethylpiperidin-4-yl]indoline,
(67) 1-(1-pyrazinylethylpiperidin-4-yl)indoline,
(68) 1-{1-[2-(4-bromopyrazol-1-yl)ethyl]piperidin-4-yl}indoline,
(69) 1-{1-[3-(4-fluorophenoxy)propyl]piperidin-4-yl}indoline,
(70) 1-{1-[3-(4-hydroxymethylphenoxy)propyl]piperidin-4-yl}indoline,
(71) 1-{1-[3-(4-hydroxyethylphenoxy)propyl]piperidin-4-yl}indoline,
(72) 1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}indoline,
(73) 1-{1-[4-(4-fluorophenyl)-4-hydroxybutyl]piperidin-4-yl}indoline,
(74) 1-[1-(phthalimido-1-yl)ethylpiperidin-4-yl]indoline,
(75) 1-[1-(4-fluorobenzamido)ethylpiperidin-4-yl]indoline,
(76) 1-{1-[1-(3,4-dimethoxyphenyl)propan-2-yl]piperidin-4-yl}indoline,
(77) 1-{1-[(1,4-benzodioxan-2-yl)methyl]piperidin-4-yl}indoline,
(78) 1-{1-[3-(3,4-methylenedioxyphenoxy)propyl]piperidin-4-yl}indoline,
(79) 1-[1-(4-fluorophenethyl)-3-methylpiperidin-4-yl]indoline,
(80) 1-(1-benzyl-3-hydroxymethylpiperidin-4-yl)indoline,
(81) 1-[1-(4-fluorophenethyl)-3-hydroxymethylpiperidin-4-yl]indoline,
(82) 1-[1-(4-fluorophenethyl)-3-hydroxymethylpiperidin-4-yl]indoline,
(83) 1-[2-(4-acetamidomethylphenyl)ethyl]-4-(indan-1-yl)piperidin-1-oxide,
(84) 1-[1-ethyl-3-(4-fluorophenoxymethyl)piperidin-4-yl]indoline,
(85) 1-[1-ethyl-3-(4-fluorobenzyloxymethyl)piperidin-4-yl]indoline,
(86) 1-[1-ethyl-3-(4-fluorobenzyloxymethyl)piperidin-4-yl]indoline,
(87) 1-(1-acetylpiperidin-4-yl)indoline-7-carbaldehyde,
(88) 1-[1-(4-t-butoxycarbonyl)piperidin-4-yl]-6-bromoindoline,
(89) 1-[1-(4-t-butoxycarbonyl)piperidin-4-yl]-6-hydroxymethylindoline,
(90) 1-[1-(4-t-butoxycarbonyl)piperidin-4-yl]-6-aminomethylindoline,
(91) 1-(1-benzylpiperidin-4-yl)-6-bromoindoline,
(92) 1-(1-benzylpiperidin-4-yl)-6-fluoroindoline,
(93) 1-(1-benzylpiperidin-4-yl)-6-formylindoline,
(94) 1-(1-benzylpiperidin-4-yl)-6-hydroxyiminomethylindoline,
(95) 1-(1-benzylpiperidin-4-yl)-6-aminomethylindoline,
(96) 1-(1-benzylpiperidin-4-yl)-6-acetamidomethylindoline,
(97) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-acetamidomethylindoline,
(98) 1-[1-(4-chlorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,
(99) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-5-methoxyindoline,
(100) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline,
(101) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline,
(102) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloroindoline,
(103) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoroindoline,
(104) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyindoline,
(105) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-4-methoxyindoline,
(106) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline,
(107) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-methoxyindoline,
(108) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6,7-dimethoxyindoline,
(109) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-nitroindoline,
(110) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminoindoline,
(111) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methylaminoindoline,
(112) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ethylaminoindoline,
(113) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isopropylaminoindoline,
(114) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-dimethylaminoindoline,
(115) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoindoline,
(116) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonylaminoindoline,
(117) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ethanesulfonylaminoindoline,
(118) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-propanesulfonylaminoindoline,
(119) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-fluorobenzenesulfonylamino)indoline,
(120) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylmethanesulfonylamino)indoline,
(121) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyethoxyindoline,
(122) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonyloxyindoline,
(123) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-hydroxyethoxyindoline,
(124) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanoindoline,
(125) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylindoline,
(126) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-pyrrolylcarbonyl)indoline,
(127) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetylindoline,
(128) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonylindoline,
(129) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-thiocarbamoylmethylindoline,
(130) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline,
(131) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindoline,
(132) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6aminomethylindoline,
(133) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,
(134) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,
(135) 1-[1-(3-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,
(136) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline,
(137) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyethyl)indoline,
(138) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxypropyl)indoline,
(139) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-1-methylethyl)indoline,
(140) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxycyclobutyl)indoline,
(141) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxycyclopentyl)indoline,
(142) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline,
(143) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoromethylindoline,
(144) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-fluoroethyl)indoline,
(145) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanomethylindoline,
(146) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline,
(147) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindoline,
(148) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(methylcarbamoylmethyl)indoline,
(149) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(ethylcarbamoylmethyl)indoline,
(150) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-propylcarbamoylmethyl)indoline,
(151) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(isopropylcarbamoylmethyl)indoline,
(152) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(isobutylcarbamoylmethyl)indoline,
(153) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(t-butylcarbamoylmethyl)indoline,
(154) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(cyclopropylcarbamoylmethyl)indoline,
(155) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6(tetramethylenecarbamoylmethyl)indoline,
(156) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-propionylaminomethylindoline,
(157) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-butyryl)aminomethylindoline,
(158) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isobutyrylaminomethylindoline,
(159) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyclopropanecarboxamidomethylindoline,
(160) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methylsulfonylaminomethylindoline,
(161) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ureidomethylindoline,
(162) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylaminomethylindoline,
(163) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylacetamidomethylindoline,
(164) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylsulfamoylmethyl)indoline,
(165) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-acetamidoethyl)indoline,
(166) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoethylindoline,
(167) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(piperidin-4-yl)methyl]indoline,
(168) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(1-acetylpiperidin-4-yl)methyl]indoline,
(169) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(1-ethylpiperidin-4-yl)methyl]indoline,
(170) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(1-methylpiperidin-4-yl)methyl]indoline,
(171) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyridyl)indoline,
(172) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-thiazolyl)indoline,
(173) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-methylpyrrol-2-yl)indoline,
(174) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)methyl]indoline,
(175) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(2-pyridyl)methyl]indoline,
(176) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(3-pyridyl)methyl]indoline,
(177) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(3-pyridyl)methyl]indoline,
(178) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-4-pyridylmethyl)indoline,
(179) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-pyridylmethyl)indoline,
(180) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyridylcarbonyl)indoline,
(181) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridyl)ethyl]indoline,
(182) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(2-pyridyl)ethyl]indoline,
(183) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-pyridylcarbonyl)indoline,
(184) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-3-yl)methyl]indoline,
(185) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(2-methoxypyridin-3-yl)methyl]indoline,
(186) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-6-yl)methyl]indoline,
(187) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(2-methoxypyridin-6-yl)methyl]indoline,
(188) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-methoxypyridin-5-yl)methyl]indoline,
(189) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(2-methoxypyridin-5-yl)methyl]indoline,
(190) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyridon-5-yl)methyl]indoline,
(191) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-dimethylaminopyridin-5-yl)methyl]indoline,
(192) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-chloropyridin-5-yl)methyl]indoline,
(193) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(2-thiazolyl)-1-hydroxymethyl]indoline,
(194) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-thiazolylcarbonyl)indoline,
(195) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(4-thiazolyl)-1-hydroxymethyl]indoline,
(196) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(5-thiazolyl)-1-hydroxymethyl]indoline,
(197) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(pyrimidin-2-yl)methyl]indoline,
(198) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(pyrimidin-5-yl)methyl]indoline,
(199) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-hydroxy-1-(2-pyrrolyl)methyl]indoline,
(200) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N,N-dimethylaminomethylindoline,
(201) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-fluorophenyl)indoline,
(202) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyrrolidon-1-yl)methylindoline,
(203) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-piperidon-1-yl)methylindoline,
(204) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(succinimido-1-yl)methylindoline,
(205) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(glutarimido-1-yl)methylindoline,
(206) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-imidazolidonyl)methylindoline,
(207) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2,4-imidazolidinedion-3-yl)methylindoline,
(208) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-oxazolidon-3-yl)methylindoline,
(209) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2,4-thiazolidinedion-3-yl)methylindoline,
(210) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(pyrrol-1-yl)methylindoline,
(211) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(imidazol-1-yl)methylindoline,
(212) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2,3-triazol-1-yl)methylindoline and 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2,3-triazol-2-yl)methylindoline,
(213) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2,4-triazol-2-yl)methylindoline,
(214) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-thiazolyl)methylindoline,
(215) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-(4-methoxybenzyl)indoline,
(216) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-methylindoline,
(217) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-5-chloro-6-aminoindoline,
(218) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-5-chloro-6-methanesulfonylaminoindoline,
(219) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-5-chloro-6-methoxyindoline,
(220) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-aminoindoline,
(221) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-methanesulfonylaminoindoline,
(222) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-acetamidoindoline,
(223) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl -6-bromoindoline,
(224) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,
(225) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindoline,
(226) 1-{1-[3-(4-fluorophenyl)propyl]piperidin-4-yl}-6-acetamidomethylindoline,
(227) 1-{1-[4-(4-fluorophenyl)butyl]piperidin-4-yl}-6-acetamidomethylindoline,
(228) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-methoxyindoline,
(229) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-fluoroindoline,
(230) 1-[1-(4-sulfamoylphenethyl)piperidin-4-yl]-6-methoxyindoline,
(231) 1-[1-(4-fluorophenoxypropyl)piperidin-4-yl]-6-bromoindoline,
(232) 1-[1-(4-fluorophenoxypropyl)piperidin-4-yl]-6-acetamidomethylindoline,
(233) 1-{1-[2-(6-benzothiazolyl)ethyl]piperidin-4-yl}-6-methoxyindoline,
(234) 1-[1-(4-fluorophenethyl)piperidin-4-yl]thiazolo[5,4-f]indoline,
(235) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminothiazolo[5,4-f]indoline,
(236) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-hydroxy-(4a,7a)-cyclohexanoindoline and 1-[1-(4-fluorophenethyl)piperidin-4-yl]-4-hydroxy-(3b,6a)-cyclohexanoindoline,
(237) 1-(1-methylpiperidin-4-yl)-6-(4-fluorobenzene-sulfonylamino)indoline,
(238) 1-(1-ethylpiperidin-4-yl)-6-(4-fluorobenzene-sulfonylamino)indoline,
(239) 1-(1-ethylpiperidinyl)-4-(4-fluorophenyl)indoline,
(240) 1-(1-ethylpiperidin-4-yl)-3-(4-fluorophenyl)-indoline,
(241) 1-(1-ethylpiperidin-4-yl)-3-(4-methoxyphenyl)-indoline,
(242) 1-(1-ethylpiperidin-4-yl)-3-(4-methoxybenzyl)-indoline,
(243) 1-[(1-ethylpiperidin-4-yl)methyl]-3-(4-methoxy-benzyl)indoline,
(244) 1-(1-ethylpiperidin-4-yl)-3-(4-fluorobenzyl)-indoline,
(245) 1-(1-ethylpiperidin-4-yl)-3-(3-pyridylmethyl)-indoline,
(246) 1-(1-ethylpiperidin-4-yl)-3-(3-methoxyphenethyl)-indoline,
(247) 1-(1-ethylpiperidin-4-yl)-3-(3-fluorophenethyl)-indoline,
(248) 1-[1-(4-fluorophenethyl)piperidin-4-yl]indan,
(249) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]indan,
(250) 1-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-6-methoxyindan,
(251) 1-(4-ethylpiperazin-1-yl)-6-methoxyindan,
(252) 1-(4-ethylpiperazin-1-yl)-2-ethoxycarboxyaminoindan,
(253) 1-(4-ethylpiperazin-1-yl)-2-methylaminoindan,
(254) 1-(4-ethylpiperazin-1-yl)-2-[methyl-(4-trifluorobenzyl)amino]indan,
(255) 7-[4-hydroxy-1-(4-fluorophenethyl)piperidin-4-yl]-5,6-dihydro-7H-pyrindine,
(256) 7-[1-(4-fluorophenethyl)piperidin-4-ylidene]-5,6-dihydropyrindine,
(257) 7-[1-(4-fluorophenethyl)piperidin-4-yl]-5,6-dihydro-7H-pyrindine,
(258) 7-[4-(4-fluorophenethyl)piperazin-1-yl]-5,6-dihydro-7H-pyrindine,
(259) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloro-7-azaindoline,
(260) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-7-azaindoline,
(261) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoro-7-azaindoline,
(262) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-chloro-7-azaindoline,
(263) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-chloro-7-azaindoline,
(264) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-azaindoline,
(265) 5-[1-(4-fluorophenethyl)piperidin-4-ylidene]-7-methyl-5,6-dihydrocyclopentapyrazine,
(266) 5-[1-(4-fluorophenethyl)piperidin-4-yl]-7-methyl-5,6-dihydro-5H-cyclopentapyrazine,
(267) 1-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,
(268) 1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,
(269) 1-[1-(4-cyanopropyl)piperidin-4-yl]-7-methoxy-1,2,3,4-tetrahydroquinoline,
(270) 1-{1-[2-(2-thienyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,
(271) 1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7,8-dimethoxy-1,2,3,4-tetrahydroquinoline,
(272) 1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7,8-methylenedioxy-1,2,3,4-tetrahydroquinoline,
(273) 1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl}-7-methoxy-8-methyl-1,2,3,4-tetrahydroquinoline,
(274) 1-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,
(275) 1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,
(276) 1-{1-[2-(4-fluorophenyl)-2-fluoroethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline,
(277) 1-[2-(4-fluorophenyl)ethyl]-4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine,
(278) 1-[2-(4-fluorophenyl)ethyl]-4-[6-(2-hydroxy)ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]piperidine,
(279) trans-1-(4-ethylpiperazin-1-yl)-7-methoxy-2-(4-trifluoromethylphenoxy)-1,2,3,4-tetrahydronaphthalene,
(280) 1-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-7-methoxy-1,2,3,4-tetrahydronaphthalene,
(281) 1-{4-[2-(4-fluorophenyl)-2-oxoethyl]piperazin-1-yl}-7-methoxy-1,2,3,4-tetrahydronaphthalene,
(282) 1-(4-fluorophenethyl)-4-(2-methoxybenzocycloheptan-9-yl)piperazine,
(283) 5-{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydroisoquinoline,
(284) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-5,6-methylenedioxyindoline,
(285) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,
(286) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-isopropylcarbamoylmethyl)indole,
(287) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-methylpyrrol-2-yl)indole,
(288) 1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indole,
(289) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanoindole,
(290) 1-[1-(4-fluorophenethyl)-3-methylpiperidin-4-yl]indole,
(291) 1-[1-(4-fluorophenethyl)homopiperidin-4-yl]-6-methoxyindoline,
(292) 1-[1-(4-fluorophenethyl)pyrrolidin-3-yl]-6-methoxyindoline,
(293) 3,3-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline,
(294) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(ethylcarbamoylmethyl)indole,
(295) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[N-(cyclopropylcarbamoyl)methyl]indole,
(296) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[N-(isobutylcarbamoyl)methyl]indole,
(297) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-propylcarbamoylmethyl)indole,
(298) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(tetramethylenecarbamoylmethyl)indole,
(299) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindole,
(300) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-hydroxyethyl)carbamoylmethylindole,
(301) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-dimethylcarbamoylmethylindole,
(302) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-hydroxypiperidin-1-ylcarbonylmethyl)indole,
(303) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[bis(2-hydroxyethyl)carbamoylmethyl]indole,
(304) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,3-dihydroxypropan-2-yl)carbamoylmethylindole,
(305) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylmethylindole,
(306) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(carbamoylmethyl)carbamoylmethylindole,
(307) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-dimethylaminoethyl)carbamoylmethylindole,
(308) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanomethylcarbamoylmethylindole,
(309) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-methoxyethyl)carbamoylmethylindole,
(310) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-fluoroethyl)carbamoylmethylindole,
(311) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(ethylcarbamoyl)ethyl]indole,
(312) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(pyrrolidin-1-yl)ethyl]carbamoylmethylindole,
(313) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(morpholin-4-yl)ethyl]carbamoylmethylindole,
(314) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(pyridin-4-yl)methylcarbamoylmethylindole,
(315) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[2-(pyridin-2-yl)ethyl]carbamoylmethylindole,
(316) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethylindole,
(317) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-methoxypyridin-5-ylcarbonyl)indole,
(318) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(2-methoxypyridin-5-yl)hydroxymethyl]indole,
(319) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyproyl)indole,
(320) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxy-1-methylethyl)indoline,
(321) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-hydroxypropyl)indole,
(322) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonamidomethylindole,
(323) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isopropylsulfonamidomethylindole,
(324) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-n-propylsulfonamidomethylindole,
(325) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-chloropropyl)sulfonamidomethylindole,
(326) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,3-propanesultam-2-yl)methylindole,
(327) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-propionylaminomethylindole,
(328) 3-chloro-1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-acetamidomethylindole,
(329) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(4-hydroxybutyroylamidomethyl)indole,
(330) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyethoxyindole,
(331) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonylindole,
(332) 1-[1-(2,6-difluoro-3-pyridylethyl)piperidin-4-yl]indole,
(333) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoroindole,
(334) 1-[1-(4-fluorophenethyl)piperidin-4-yl]thiazolo-[5,4-f]indole,
(335) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylmethanesulfonylamino)indole,
(336) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonyloxyindole,
(337) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylindole,
(338) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N-methylsulfamoylmethyl)indole,
(339) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoindole,
(340) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,2-dihydroxypropan-3-yl)carbamoylmethylindole,
(341) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(pyridin-2-yl)methylcarbamoylmethylindole,
(342) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethylindole,
(343) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(1-acetylpiperidin-4-yl)methylcarbamoylmethylindole,
(344) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-ethylcarbamoylmethylindole,
(345) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-ethylpiperidin-4-yl)methylcarbamoylmethylindole,
(346) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(2-hydroxyethyl)carbamoylmethylindole,
(347) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1,3-dioxolan-2-ylmethyl)carbamoylmethylindole,
(348) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole,
(349) 1-[1-(4-chlorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,
(350) 1-[1-(3-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,
(351) 1-[1-(4-methoxyphenethyl)piperidin-4-yl]-6-acetamidomethylindole,
(352) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,
(353) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2,4-imidazolidinedion-3-yl)methylindole,
(354) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-isobutyrylaminomethylindole,
(355) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-imidazolidonyl)methylindole,
(356) 1-{1-[4-(4-fluorophenyl)butyl]piperidin-4-yl}-6-acetamidomethylindole,
(357) 1-[1-(2,4-difluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,
(358) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(2-pyrrolidon-1-yl)methylindole,
(359) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylacetamidomethylindole,
(360) 1-{1-[3-(4-fluorophenyl)propyl]piperidin-4-yl}-6-acetamidomethylindole,
(361) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylaminomethylindole,
(362) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-butyryl)aminomethylindole,
(363) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyclopropanecarboxamidomethylindole,
(364) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyacetamidomethylindole,
(365) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-difluoroacetamidomethylindole,
(366) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-fluoroacetamidomethylindole,
(367) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-chloropropionylamino)methylindole,
(368) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-imidazocarbonylaminomethylindole,
(369) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-hydroxypropionylamino)methylindole,
(370) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-formyl-6-acetamidomethylindole,
(371) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-hydroxyimino-6-acetamidomethylindole,
(372) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-3-hydroxymethyl-6-acetamidomethylindole,
(373) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloroacetamidomethylindole,
(374) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoacetamidomethylindole,
(375) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(N,N-dimethylaminoacetamido)methylindole,
(376) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(piperidin-1-yl)acetamido]methylindole,
(377) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-bromopropionylamino)methylindole,
(378) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-N,N-dimethylaminopropionyl)aminomethylindole,
(379) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[3-(piperidin-1-yl)propionylamino]methylindole,
(380) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-propionylaminomethylindole,
(381) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-fluoroacetamidomethylindole,
(382) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(3-hydroxypropionylamino)methylindole,
(383) 1-(1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxyacetamidomethylindole,
(384) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxycarbonylaminomethylindole,
(385) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N,N-dimethylaminocarbonylaminomethylindole,
(386) 1-{1-[2-(3-pyridyl)ethyl]piperidin-4-yl}-6-acetamidomethylindole,
(387) 3-cyano-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindole,
(388) 1-{4-[(1-hydroxyethyl)phenethyl]piperidin-4-yl}-6-acetamidomethylindole,
(389) 1-[1-(4-bromophenethyl)piperidin-4-yl]-6-acetamidomethylindole,
(390) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-formylindole,
(391) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindole,
(392) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyethyl)indole,
(393) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ureidomethylindole,
(394) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-methylureido)methylindole,
(395) 3,3-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidoindoline,
(396) 2,2-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline and
(397) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-methylureido)methylindole.
Although some of the 1,4-substituted cyclic amine derivatives (I) of the present invention occur as optical isomers or geometrical isomers, either one of these optical isomers or a mixture thereof may be used in the present invention without restriction. Similarly, either one of geometrical isomers or a mixture thereof may be employed herein without any restriction. In the case of polymorphic crystals, either one of the crystal forms or a mixture thereof may be used in the present invention without restriction, too. Moreover, use may be made of both anhydrides and hydrates.
The pharmacologically acceptable salts to be used in the present invention may be arbitrary salts of the 1,4-substituted cyclic amine derivatives (I) of the present invention without particular restriction. Examples thereof include inorganic acid addition salts such as hydrochlorides, sulfates, nitrates, hydrobromides, hydriodides, perchlorates and phosphates, organic acid addition salts such as oxalates, maleates, fumarates and succinates, sulfonic acid addition salts such as methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates and camphorsulfonates, and amino acid addition salts. Among all, it is preferable to use hydrochlorides and oxalates thereof.
The 1,4-substituted cyclic amine derivative (II) according to the present invention is represented by the following formula: 
R represents a substituent selected from among the following ones: 
(wherein the bond represented by the following formula: 
xe2x80x83and R1, R2 and R3 are each as defined above); and
R4, R5, Y, Z, m and p are each as defined above.
Examples of the 1,4-substituted cyclic amine derivatives (II) include compounds similar to those cited above as the examples of the 1,4-substituted cyclic amine derivatives (I), though the present invention is not restricted thereto.
The 1,4-substituted cyclic amine derivative (III) according to the present invention is represented by the following formula: 
wherein the bond represented by the following formula: 
and R1, R2, R3, R4 and R5 are each as defined above.
Further, the 1,4-substitutedcyclic amine derivative (IV) of the present invention is represented by the following formula: 
wherein the bond represented by the following formula: 
and R1, R2, R3, R4, R6, Q1, Q2 and s are each as defined above.
Next, the 1,4-substituted cyclic amine derivative (V) according to the present invention is represented by the following formula: 
wherein R1, R2, R3, R4, R6 and s are each as defined above.
Finally, the 1,4-substituted cyclic amine derivative (VI) according to the present invention is represented by the following formula: 
wherein R1, R2, R3, R4, R6 and s are each as defined above.
Among the 1,4-substituted cyclic amine derivatives (I) to (VI) according to the present invention, those which are particularly preferable from the viewpoint of pharmacological effects or safety are, for example, the following ones:
(1) 1-[1-(4-acetamidomethylphenethyl)piperidin-4-yl]indoline,
(2) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carbamoylindoline,
(3) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methanesulfonylindoline,
(4) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-acetamidomethylindoline,
(5) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-hydroxyethyl)indoline,
(6) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(n-propylcarbamoylmethyl)indoline,
(7) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(isopropylcarbamoylmethyl)indoline,
(8) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ureidomethylindoline,
(9) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-N-methylacetamidomethylindoline,
(10) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[1-(4-thiazolyl)-1-hydroxymethyl]indoline, and
(11) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6acetamidomethylindole.
The compounds of the present invention are each a highly safe one having an extremely high LD50.
Although compounds having the indoline or indan skeleton are disclosed in WO96/23784, JP-A 8-512,299 (WO95/01976), WO97/06155, etc., these compounds are completely different in structure from the 1,4-substituted cyclic amine derivatives (I) to (VI) of the present invention.
The present invention provides the method for treating the disease which serotonin antagonism is efficacious, by administering the effective dose of the compound as set forth or pharmacologically acceptable salts thereof to a person, and the use of the compound as set forth or pharmacologically acceptable salts thereof for treating the disease which serotonin antagonism is efficacious.
The present invention includes the following mode:
(1) 1,4-Substituted cyclic amine derivatives, which the bond represented by the following formula in the formula (I): 
is a single bond, represented by the formula (XXI): 
or pharmacologically acceptable salts thereof.
(2) 1,4-Substituted cyclic amine derivatives, which m is 0 in the formula (I), represented by the formula (XXII): 
or pharmacologically acceptable salts thereof.
(3) 1,4-Substituted cyclic amine derivatives represented by the formula (I), in which m is 1 to 6 selected from the following compounds:
(16) 1-[1-(4-fluorophenethyl)piperidin-4-yl]methylindoline,
(17) 1-{2-[1-(4-fluorophenethyl)piperidin-4-yl]ethyl}indoline, and
(243) 1-[(1-ethylpiperidin-4-yl)methyl]-3-(4-methoxybenzyl)indoline
or pharmacologically acceptable salts thereof.
(4) 1,4-Substituted cyclic amine derivatives represented by the formula (XXIII): 
xe2x80x83selected from the following compounds:
(256) 7-[1-(4-fluorophenethyl)piperidin-4-ylidene]-5,6-dihydropyrindine and
(265) 5-[1-(4-fluorophenethyl)piperidin-4-ylidene]-7-methyl-5,6-dihydrocyclopentapyrazine
or pharmacologically acceptable salts thereof.
(5) 1,4-Substituted cyclic amine derivatives, which the bond represented by the following formula in the formula (I):. 
is a double bond, represented by the formula (XXIV): 
or pharmacologically acceptable salts thereof.
The 1,4-substituted cyclic amine derivatives (I) of the present invention can be produced by, for example, the following processes, though the present invention is not restricted thereto.
(1) The Case where T=N, m=0, Y=Methine, and Z=N
In this case, the aimed compounds can be synthesized in accordance with the conventional method of reductive amination, for example, the one described in xe2x80x9cShin Jikken Kagaku Koza 14-IIIxe2x80x9d, p. 1380 (Maruzen Co., Ltd.), by reacting a fused cyclic amine (VII) with a cyclic ketone (VIII) in the presence of a reducing agent to thereby give a 1,4-substituted cyclic amine derivative (IX), removing the protecting group therefrom if necessary, and then introducing a substituent R5 thereinto. This reaction is represented by the following chemical reaction formula: 
[wherein the bond represented by the following formula: 
represents a single or double bond;
A, B, C, D, R1, R2, R3, R4, R5, n and p are each as defined above; Pr.G represents hydrogen or a protecting group; and L represents a leaving group such as hydroxy, halogeno or methanesulfonyloxy].
It is also possible to chemically modify the substituents R1, R2, R3 and R4 to thereby synthesize analogs of the 1,4-substituted cyclic amine derivatives.
The reducing agent to be used herein may be an arbitrary one, so long as it is one commonly employed in reductive N-alkylation. Preferable examples thereof include sodium triacetoxyborohydride, sodium cyanoborohydride and lithium aluminum hydride.
(2) The Case where T=N, n=0, m=0, Y=Methine, and Z=N
An alternative method of (1) for synthesizing, in particular, the 1,4-substituted cyclic amine derivatives (I) wherein n=0 comprises treating the amine (XI) successively with oxalyl chloride and aluminum chloride to thereby give a diketone (XII), reducing the same to thereby give an indole derivative (XIII), removing the protecting group therefrom if necessary, then introducing a substituent R5 thereinto to thereby give an indole derivative (XIV), and reducing the same to thereby give an indoline derivative (XV). This reaction is represented by the following chemical reaction formula: 
[wherein the bond represented by the following formula: 
and A, B, C, D, R1, R2, R4, R5, p, Pr.G and L are each as defined above.]
(3) The Case of Indole Derivatives wherein T=N, n=0, m=0, Y=Methine, and Z=N
The indole derivatives (XIV) can be obtained not only by the above method (2) but also by oxidizing the indoline derivatives (XV) in a conventional manner. Although the reagent and catalyst to be used in such a case are not particularly restricted, it is preferable to use activated manganese dioxide. 
(4) The Case where T=Methine, n=0, m=0, Y=Methine, and Z=N
The aimed compounds can be synthesized by introducing a substituent R5 into 1-(piperidin-4-yl) indan derivatives (XVI). This reaction is represented by the following chemical reaction formula: 
[wherein the bond represented by the following formula: 
and A, B, C, D, R1, R2, R4, R5, p and L are each as defined above.]
(5) The Case where T=N, n=1, m=0, Y=Methine, and Z=N
The aimed compounds can be synthesized by introducing a substituent R5 into 1-(4-piperidinyl)-1,2,3,4-tetrahydroquinoline derivatives (XVIII). This reaction is represented by the following chemical reaction formula: 
[wherein the bond represented by the following formula: 
and A, B, C, D, R1, R2, R3, R4, R5, p and L are each as defined above.]
Among the 1,4-substituted cyclic amine derivatives (I) according to the present invention, compounds having structures other than those as defined in the above cases (1) to (4) can be produced by the same methods as the ones as will be described in Examples hereinafter.
To produce the 1,4-substituted cyclic amine derivatives (I) of the present invention, 4-substituted cyclic amine derivatives (XX) represented by the following formula are novel compounds which are useful as intermediates in the production of the 1,4-substituted cyclic amine derivatives (I) to (VI) having a serotonin antagonism and being clinically useful as medicaments for, in particular, treating, ameliorating and preventing spastic paralysis or central muscle relaxants for ameliorating myotonia: 
wherein the bond represented by the following formula: 
and A, B, C, D, R1, R2, R3, R4, n and p are each as defined above, provided that the case where R1, R2, R3 and R4 are all hydrogen is excluded.
More particularly speaking, the 4-substituted cyclic amine derivatives (XX) are exemplified by the following compounds, though the present invention is not restricted thereto:
(1) 1-(piperidin-4-yl)-6-fluoroindoline,
(2) 1-(piperidin-4-yl)-6-bromoindoline,
(3) 1-(piperidin-4-yl)-6-nitroindoline,
(4) 1-(piperidin-4-yl)-6-methoxyindoline,
(5) 1-(piperidin-4-yl)-6-acetamidomethylindoline,
(6) 1-(piperidin-4-yl)-6-fluoroindole,
(7) 1-(piperidin-4-yl)-6-bromoindole,
(8) 1-(piperidin-4-yl)-6-nitroindole,
(9) 1-(piperidin-4-yl)-6-methoxyindole, and
(10) 1-(piperidin-4-yl)-6-acetamidomethylindole.
Examples of the dosage forms of the compounds of the present invention include oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, external preparations such as ointments, patches and suppositories, and injections. These preparations may be produced by the conventional methods with the use of pharmaceutical carriers commonly employed in the art.
Namely, oral preparations may be produced by blending the 1,4-substituted cyclic amine derivative or a pharmacologically acceptable salt thereof with fillers optionally together with binders, disintegrating agents, lubricating agents, coloring agents, corrigents, etc. and then processing the resultant blends into powders, fine granules, granules, tablets, coated tablets, capsules, etc. by the conventional methods.
As the fillers, use may be made of, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide. As the binders, use may be made of, for example, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol/polyoxyethylene block polymers and meglumine. As the disintegrating agents, use may be made of, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin and calcium carboxymethylcellulose. As the lubricating agents, use may be made of, for example, magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. As the coloring agents, use may be made of those authorized as pharmaceutical additives. As the corrigents, use may be made of, for example, cocoa powder, mentha, aromatic powder, mentha oil, borneol and powdered cinnamon bark. Needless to say, these tablets and granules may be appropriately coated with sugar, etc., if necessary.
Injections are produced by blending the 1,4-substituted cyclic amine derivative or a pharmacologically acceptable salt thereof with pH regulating agents, resolvents, tonicity agents, etc., optionally together with dissolution aids, stabilizers, etc. and processing the resultant blends into preparations by the conventional methods.
External preparations may be produced by the conventional methods without restriction. As the bases, therefore, use can be made of various materials commonly used in drugs, quasi drugs, cosmetics, etc.
Particular examples of the base materials include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and purified water. If needed, it is possible to further add pH regulating agents, antioxidants, chelating agents, antiseptics, fungicides, coloring agents, perfumes, etc., though the materials usable as the base in the external preparations of the present invention are not restricted thereto. If necessary, it is also possible to furthermore add other ingredients capable of inducing differentiation, blood flow accelerators, bactericides, antiinflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents, etc. The above materials may be added in such amounts as to give the concentrations thereof commonly employed in the production of external preparations.
The clinical dose of the 1,4-substituted cyclic amine derivative of the present invention or a pharmacologically acceptable salt thereof is not restricted but varies depending on the symptoms, severity, age, complications, etc. Also, the dose thereof varies depending on the type of the salt, administration route, etc. In general, these compounds are administered to an adult in a dose of from 0.01 to 1000 mg, preferably from 0.1 to 500 mg and still preferably from 0.5 to 100 mg, per day orally, intravenously, as suppositories or percutaneously.
Next, the results of a binding test on the compounds of the present invention to serotonin 1A and serotonin 2 receptors will be given so as to illustrate the effects of the present invention. Moreover, the results of a binding test on these compounds to an al adrenalin receptor will be given so as to illustrate the safety thereof.
It is reported in, for example, the following publications that compounds with a serotonin antagonism are usable as medicament for treating, ameliorating and preventing spastic paralysis or central muscle relaxants for ameliorating myotonia:
(1) Saishin Igaku Jiten, 3rd impression of 1st edition, p. 809 xe2x80x9cSEROTONINxe2x80x9d, Iyaku Shuppan
(2) Stedman""s Medical Dictionary, 24th edition, p. 1227 xe2x80x9cserotoninxe2x80x9d, Williams and Wilkins
(3) Shinkei Shinpo, 37(3), 459-467, 1993.
(4) Iyaku Journal, 30(8), 2030-2068, 1994.
(5) DN and P, 5(8), 453-460, 1992.
(6) Annals of Neurology, 30(4), 533-541, 1991.
Compounds poor in the ability to bind to an aI adrenalin receptor are medicines which would scarcely affect blood pressure in orthostatic hypotension, etc. and have a higher safety.
(1) Binding Test on Serotonin 1A, Serotonin 2 and xcex11 Adrenalin Receptors
Method
(Reagent)
The following reagents were employed in this test.
1) Serotonin binoxalate (5-HT binoxalate, mfd. by Sigma Chemical Co.).
2) Methysergide maleate (mfd. by RBI).
As radioisotope-labeled compounds, use was made of the following reagents (mfd. by NEN).
3) [3H] 8-Hydroxy-dipropylaminotetralin (8-OH-DPAT).
4) [3H] Ketanserin hydrochloride.
5) [3H] Prazosin.
These compounds and test compounds, when insoluble in water, were dissolved in ethanol and then diluted with distilled water so as to each give an ethanol concentration of 10%. Methysergide maleate was dissolved in distilled water before using.
(Animal)
Use was made of SD rats aged 6 to 8 weeks.
(Preparation of Receptor Source)
The rats were sacrificed by dcapitation to extirpate the cerebra. The hippocampus and cortex were separated therefrom and employed in the binding tests respectively on the serotonin 1A receptor and the serotonin 2 receptor.
The hippocampus was mixed with 50 times (on the wet weight basis) as much a 0.32 M sucrose solution while the cortex was mixed with 10 times as much the same solution. Each mixture was homogenized by using a Teflon glass homogenizer and centrifuged at 1,000xc3x97g for 10 min. The supernatant thus obtained was further centrifuged at 20,000xc3x97g for 20 min. The obtained precipitate was re-suspended in 50 times (based on the intial wet weight; in the case of the hippocampus) or 10 times (in the case of the cortex) as much a 50 mM Tris hydrochloride (pH 7.4) and incubated at room temperature for 30 min. After centrifuging at 20,000xc3x97g for 20 min, the obtained precipitate was further suspended and centrifuged twice each in the same manner. The precipitate thus obtained was suspended in 100 times (based on the initial wet weight; in the case of the hippocampus) or 20 times (in the case of the cortex) as much a 50 mM Tris hydrochloride solution (pH 7.4) to thereby give a receptor fraction. This receptor fraction was stored at xe2x88x9280xc2x0 C. until using.
(Binding Test on [3H] 8-hydroxy-dipropylaminotetralin)
To the receptor fraction of the hippocampus were added a test compound and 0.5 nM of [3H] 8-hydroxy-dipropylaminotetralin and the resultant mixture was incubated at room temperature for 30 min. Next, it was filtered through a glass filter with the use of a cell harvester. After washing the glass filter with 50 mM Tris hydrochloride (pH 7.4), the radioactivity of the receptor was measured with a liquid scintillation counter.
The binding detected in the presence of 10 xcexcM of serotonin binoxalate was referred to as the nonspecific binding.
(Binding Test on [3H] Ketanserin)
To the receptor fraction of the cerebral cortex were added a test compound and 0.3 nM of [3H] ketanserin and the resultant mixture was incubated at 37xc2x0 C. for 15 min. Next, it was filtered through a glass filter with the use of a cell harvester. After washing the glass filter with 50 mM Tris hydrochloride (pH 7.4) , the radioactivity of the receptor was measured with a liquid scintillation counter. The binding detected in the presence of 1 xcexcM of methysergide was referred to as the nonspecific binding.
IC50 was calculated by the probit method, while Ki was determined in accordance with the following formula:
Ki=IC50/(1+c/Kd)
wherein c represents the concentration of the radioisotope-labeled compound, and Kd represents the dissociation constant of the radioisotope-labeled compound with respect to the receptor determined by Scatchard""s analysis.
(Binding Test on [3H] Prazosin)
To the receptor fraction of the cerebral cortex were added a test compound and about 0.2 nM of [3H] prazosin and the resultant mixture was incubated at room temperature for 60 min. Next, it was filtered through a glass filter with the use of a cell harvester. After washing the glass filter with 50 mM Tris hydrochloride (pH 7.4), the radioactivity of the receptor was measured with a liquid scintillation counter. The binding detected in the presence of 10 xcexcM of phentolamine was referred to as the nonspecific binding.
The following tables show the abilities of typical examples of the compounds of the present invention to bind to the serotonin 1A and serotonin 2 receptors, wherein the number of each compound corresponds to the Example number. Also, comparison was made with cyproheptadine hydrochloride (CAS Registry No.: 969-33-5) and cyclobenzaprine hydrochloride (CAS Registry No.: 6202-23-9) which were employed as positive controls having anti-serotonin effects.
Subsequently, the abilities of typical examples of the compounds of the present invention to bind to the xcex11 adrenalin receptor were evaluated by the test method described above. The following table shows the results, wherein the number of each compound corresponds to the Example number.
Also, comparison was made with Co. No. 5, as a typical example of the known compounds with a serotonin antagonism, disclosed in Table 2 of WO96/23784 and having the following chemical formula. This compound was produced in accordance with the method described in WO96/23784 (see Referential Example 1 as will be given hereinbelow).
Tables 1 to 6 indicate that the 1,4-substituted cyclic amine derivatives of the present invention are useful as medicaments with a serotonin antagonism and have clinical usefulness and a high safety, in particular, those for treating, ameliorating and preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
Moreover, the compounds of the present invention are superior in safety to the Co. No. 5 disclosed in WO96/23784 which is a typical example of the known compounds, since the compounds in the present invention have low abilities to bond to the xcex11 adrenalin receptor and scarcely affect blood pressure.
(2) Morphine Induced Straub""s Tail Phenomenon in Mice
By using mice, typical examples of the compounds of the present invention were evaluated in the effect of relaxing rigidity in accordance with the method reported in Drug Dev. Res., 11:53-57, 1987.
In this test, use was made of male ddY mice aged 4 to 5 weeks (SLC, Shizuoka) which were divided into groups each comprising 8 animals. Also, use was made, as positive controls, of cyproheptadine hydrochloride, cylcobenzaprine hydrochloride, tizanidine hydrochloride (CAS Registry No.: 51322-75-9) and baclofen (CAS Registry No.: 1134-47-0). The test compounds and the positive controls were each dissolved in a 5% glucose solution for injection or suspended in a 0.5% methylcellulose solution. Morphine hydrochloride was dissolved in physiological saline for injection.
The test compounds of the given concentrations were administered per os (p.o.) or intraperitoneally (i.p.) to the mice, while the media were orally administered to the control group. After 15min of the administration of the test compounds, 12.5 mg/kg of morphine hydrochloride was subcutaneously injected into the animals. After 15, 30 and 45 min of the administration of morphine hydrochloride, the hyper-muscle tone in the tail was observed and those showing hyper-muscle tone were judged as positive in Straub""s tail reaction.
The rate of those showing Straub""s tail reaction in each test group was compared with that of the control group at each observation point and analyzed by the "khgr" square calibration method to thereby determine the statistically significant (p less than 0.05) minimal effective dose.
Now, the results of the evaluation will be shown.
As Table 7 clearly shows, the compounds of the present invention have excellent effects of relaxing rigidity in vivo.